The book of Matthew 'On naval timber and arboriculture'. Its structure and development.

The book of Patrick Matthew (1790-1874) 'On Naval Timber and Arboriculture' has regularly thwarted readers' attempts of interpretation. The problems seem to extend beyond analysing and interpreting its evolutionary passages. Building upon previous studies, this analysis presents evidence that the book's structure itself may have contributed significantly to its reception by sundry readers as somehow either clear or obscure, consequently leading to a diversity of interpretations. First, the book does not have a consistent literary form. Second, it presents a miscellany of juxtaposed contents. Third, its readers approach it from different contexts. Internal evidence shows that Patrick Matthew added a lot of material, while the manuscript was already in the proof-reading or press stage. This explains why it provides no consistent literary form or integrated content that would have helped interpretation. Hence readers have been left to their own devices, and their interpretation depended more strongly than usual on their own contexts.

Charles Darwin did not mislead Joseph Hooker in their 1881 Correspondence about Leopold von Buch and Karl Ernst von Baer.

While Joseph Hooker was considering his upcoming presentation on the geographical distribution of species, he asked Charles Darwin for help with some references. During the ensuing exchange of correspondence, Darwin seems to have contradicted himself, regarding his being aware of Leopold von Buch's observation that distributed varieties become species, prior to writing On the Origin of Species. Literalists and conspiracists have interpreted this apparent self-contradiction as a sign of duplicity and fraud. However, when the correspondence and Hooker's address are analysed in context, there is a more compelling explanation. Simply that, in response to direct questioning by Hooker, Darwin conflated the two names of Von Baer and Von Buch, and made an honest mistake.

Mutations in a delta 8-delta 7 sterol isomerase in the tattered mouse and X-linked dominant chondrodysplasia punctata. jderry@immunex.com.

Tattered (Td) is an X-linked, semi-dominant mouse mutation associated with prenatal male lethality. Heterozygous females are small and at 4-5 days of age develop patches of hyperkeratotic skin where no hair grows, resulting in a striping of the coat in adults. Craniofacial anomalies and twisted toes have also been observed in some affected females. A potential second allele of Td has also been described. The phenotype of Td is similar to that seen in heterozygous females with human X-linked dominant chondrodysplasia punctata (CDPX2, alternatively known as X-linked dominant Conradi-Hünermann-Happle syndrome) as well as another X-linked, semi-dominant mouse mutation, bare patches (Bpa). The Bpa gene has recently been identified and encodes a protein with homology to 3beta-hydroxysteroid dehydrogenases that functions in one of the later steps of cholesterol biosynthesis. CDPX2 patients display skin defects including linear or whorled atrophic and pigmentary lesions, striated hyperkeratosis, coarse lusterless hair and alopecia, cataracts and skeletal abnormalities including short stature, rhizomelic shortening of the limbs, epiphyseal stippling and craniofacial defects (MIM 302960). We have now identified the defect in Td mice as a single amino acid substitution in the delta8-delta7 sterol isomerase emopamil binding protein (Ebp; encoded by Ebp in mouse) and identified alterations in human EBP in seven unrelated CDPX2 patients.

Chromosomal localization of GABAA receptor subunit genes: relationship to human genetic disease.

Hybridization of GABAA receptor probes to human chromosomes in situ and to DNA from sorted human chromosomes has localized the genes encoding a beta subunit and three isoforms of the alpha subunit. The alpha 2 and beta genes are both located on chromosome 4 in bands p12-p13 and may be adjacent. The alpha 1 gene is on chromosome 5 (bands q34-q35) and the alpha 3 gene is on the X chromosome. The alpha 3 locus was mapped also on the mouse X chromosome using genetic break-point analysis in an interspecies pedigree. The combined results locate the human alpha 3 gene within band Xq28, in a location that makes it a candidate gene for the X-linked form of manic depression.

Sik (BRK) phosphorylates Sam68 in the nucleus and negatively regulates its RNA binding ability.

Sik (mouse Src-related intestinal kinase) and its orthologue BRK (human breast tumor kinase) are intracellular tyrosine kinases that are distantly related to the Src family and have a similar structure, but they lack the myristoylation signal. Here we demonstrate that Sik and BRK associate with the RNA binding protein Sam68 (Src associated during mitosis, 68 kDa). We found that Sik interacts with Sam68 through its SH3 and SH2 domains and that the proline-rich P3 region of Sam68 is required for Sik and BRK SH3 binding. In the transformed HT29 adenocarcinoma cell cell line, endogenous BRK and Sam68 colocalize in Sam68-SLM nuclear bodies (SNBs), while transfected Sik and Sam68 are localized diffusely in the nucleoplasm of nontransformed NMuMG mammary epithelial cells. Transfected Sik phosphorylates Sam68 in SNBs in HT29 cells and in the nucleoplasm of NMuMG cells. In functional studies, expression of Sik abolished the ability of Sam68 to bind RNA and act as a cellular Rev homologue. While Sam68 is a substrate for Src family kinases during mitosis, Sik/BRK is the first identified tyrosine kinase that can phosphorylate Sam68 and regulate its activity within the nucleus, where it resides during most of the cell cycle.

A study of information seeking by cancer patients and their carers.

AIMS: To examine cancer patients' and carers' use of, and attitudes to, the Internet as an information source compared with other media. MATERIALS AND METHODS: The study was carried out in two phases: in phase I, interviews were used to construct a suitable instrument. In phase II, interviews were completed with 800 recently diagnosed patients and 200 carers. RESULTS: Relatively few patients (4.8%), but a high proportion of carers (48%), accessed the Internet directly for cancer information. However, around half of the patients used Internet information provided by someone else, generally a family member. The use of Internet information was uniformly low among ethnic minorities. Those who accessed Internet information reported high levels of satisfaction and generally rated it higher than booklets or leaflets. When asked who they would like to provide Internet information, overwhelmingly patients wanted the hospital doctor to do so. When this was done, there was very high compliance. Carers were much more proactive information seekers than patients. CONCLUSIONS: The Internet is an effective means of information provision in those who use it. Facilitated Internet access and directed use by health professionals would be effective ways of broadening access to this medium.

Sox5 regulates beta-cell phenotype and is reduced in type 2 diabetes.

Type 2 diabetes (T2D) is characterized by insulin resistance and impaired insulin secretion, but the mechanisms underlying insulin secretion failure are not completely understood. Here, we show that a set of co-expressed genes, which is enriched for genes with islet-selective open chromatin, is associated with T2D. These genes are perturbed in T2D and have a similar expression pattern to that of dedifferentiated islets. We identify Sox5 as a regulator of the module. Sox5 knockdown induces gene expression changes similar to those observed in T2D and diabetic animals and has profound effects on insulin secretion, including reduced depolarization-evoked Ca2+-influx and ß-cell exocytosis. SOX5 overexpression reverses the expression perturbations observed in a mouse model of T2D, increases the expression of key ß-cell genes and improves glucose-stimulated insulin secretion in human islets from donors with T2D. We suggest that human islets in T2D display changes reminiscent of dedifferentiation and highlight SOX5 as a regulator of ß-cell phenotype and function.

Functional analysis and intracellular localization of p53 modified by SUMO-1.

p53 tumor suppressor is a subject of several post-translational modifications, including phosphorylation, ubiquitination and acetylation, which regulate p53 function. A new covalent modification of p53 at lysine 386 by SUMO-1 was recently identified. To elucidate the function of sumoylated p53, we compared the properties of wild type p53 and sumoylation-deficient p53 mutant, K386R. No differences were found between wild type p53 and K386R mutant of p53 in transactivation or growth suppression assays. Moreover, overexpression of SUMO-1 has no effect on p53-regulated transcription. Biochemical fractionation showed that sumoylated p53 is localized in the nucleus and is tightly bound to chromatin structures. p53 and SUMO-1 co-localized in PML nuclear bodies in 293 cells and the nucleoli in MCF7 and HT1080 cells. However, sumoylation-deficient p53 mutant showed a similar pattern of intranuclear localization, suggesting that SUMO-1 does not target p53 to subnuclear structures. These data indicate that SUMO-1 modification of p53 at lysine 386 may not be essential for p53's cellular localization, transcriptional activation, or growth regulation.

BRK/Sik expression in the gastrointestinal tract and in colon tumors.

Clones encoding the breast tumor kinase BRK were isolated from a normal human small intestinal cDNA library that was screened with the cDNA encoding the mouse epithelial-specific tyrosine kinase Sik. Although BRK and Sik share only 80% amino acid sequence identity, Southern blot hybridizations confirmed that the two proteins are orthologues. Sik was mapped to mouse distal chromosome 2, which shows conservation of synteny with human chromosome 20q13.3, the location of the BRK gene. BRK expression was examined in the normal gastrointestinal tract, colon tumor cell lines, and primary colon tumor samples. Like Sik, BRK is expressed in normal epithelial cells of the gastrointestinal tract that are undergoing terminal differentiation. BRK expression also increased during differentiation of the Caco-2 colon adenocarcinoma cell line. Modest increases in BRK expression were detected in primary colon tumors by RNase protection, in situ hybridization, and immunohistochemical assays. The BRK tyrosine kinase appears to play a role in signal transduction in the normal gastrointestinal tract, and its overexpression may be linked to the development of a variety of epithelial tumors.

Defining the educational needs of recent dental graduates preparing for the Membership of the Faculty of Dental Surgery examination.

OBJECTIVES: On graduation, UK dentists wishing to advance their career enter two years of general professional training aimed at consolidating their undergraduate experience. The Membership of the Faculty of Dental Surgery examination (MFDS) attests to its successful completion and is a pre-requisite for entry into training programmes which lead to specialist status. Most MFDS candidates prepare for the examination on their own while in full-time employment and many reinforce this self-directed learning with participation in short revision courses or through distance learning. Here we seek to obtain data on the specific educational needs of these individuals. METHODS: Questionnaires were used to interrogate 92 UK graduates attending short MFDS revision courses of up to 1 week's duration to identify which topic areas were perceived as particular areas of weakness. To gain greater insight into the responses obtained, 18/92 respondents were selected at random and followed up with semi-structured interviews informed by the questionnaires. RESULTS: Basic medical science, human diseases, law and ethics and health and safety regulations were the areas of weakness most frequently highlighted by the respondents. Most had undergone comprehensive courses in the first two topics; however, the interviews suggested that this was generally in the early stages of undergraduate training when they had difficulty in contextualising large quantities of new information. In the case of the latter two, teaching had been very varied and several interviewees felt that it had been inadequate. CONCLUSION: Recent graduates preparing for MFDS have clear educational needs. These data have begun to characterise the requirements of this group and may inform the planning of short revision courses designed to assist them.

Flow cytometric determination of intracytoplasmic Wiskott-Aldrich syndrome protein in peripheral blood lymphocyte subpopulations.

We have produced a novel monoclonal antibody (mAb) directed against Wiskott-Aldrich syndrome protein (WASP) by immunizing mice with the recombinant protein. The mAb designated 5A5 is highly specific to WASP and suitable for Western blot analysis and immunoprecipitation. A flow cytometric assay using the 5A5 mAb identifies expression of intracytoplasmic WASP in lymphocytes from normal individuals. Double staining analysis with cell surface CD3, CD19, and CD56, and intracytoplasmic molecules revealed WASP expression in each subpopulation. With regard to WASP expression in patients with Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT), peripheral blood mononuclear cells (PBMCs) from nine patients and Epstein-Barr virus-transformed B-lymphoblastoid cell lines from seven patients examined did not show WASP expression by flow cytometric analysis. These results were confirmed by Western blot analysis. We conclude that WASP expression in lymphocyte subpopulations from patients with WAS and XLT can be more precisely evaluated by flow cytometry as compared with Western blot analysis. This flow cytometry method is important as a supplement to Western blots, but even more important as an alternative and powerful assay that can contribute to research on WASP as well as diagnosis in a clinical setting.

A study of the percutaneous absorption from topically applied zinc oxide ointment.

The systemic absorption from topical applications of 40% zinc oxide ointment was investigated in a series of healthy subjects (phase one) and in patients receiving total parenteral nutrition (phase two). In the first phase, six subjects completed a controlled, cross-over trial involving 3 hourly serum sample determinations for zinc concentration following a massive application of 40% zinc oxide ointment and plain petrolatum ointment. There was a mean increase in serum zinc from 107.3 +/- 5.32 to 116.1 +/- 5.02 micrograms/dL 1 hr after application of 40% zinc oxide ointment (p greater than 0.05). Three patients receiving total parenteral nutrition completed phase two of the protocol in which 40% zinc oxide ointment was applied daily to a specified area of the thigh. Analysis of these patients' serum revealed that the zinc concentrations remained relatively constant over the 10-day study period. These findings suggest that topical applications of 40% zinc oxide ointment do not result in significant absorption. This study serves as a starting point for further investigations.

Auditing audits: use and development of the Oxfordshire Medical Audit Advisory Group rating system.

OBJECTIVES: To assess the value of the Oxfordshire Medical Audit Advisory Group rating system in monitoring and stimulating audit activity, and to implement a development of the system. DESIGN: Use of the rating system for assessment of practice audits on three annual visits in Oxfordshire; development and use of an "audit grid" as a refinement of the system; questionnaire to all medical audit advisory groups in England and Wales. SETTING: All 85 general practices in Oxfordshire; all 95 medical audit advisory groups in England and Wales. MAIN OUTCOME MEASURES: Level of practices' audit activity as measured by rating scale and grid. Use of scale nationally together with perceptions of strengths and weaknesses as perceived by chairs of medical audit advisory groups. RESULTS: After one year Oxfordshire practices more than attained the target standards set in 1991, with 72% doing audit involving setting target standards or implementing change; by 1993 this had risen to 78%. Most audits were confined to chronic disease management, preventive care, and appointments. 38 of 92 medical audit advisory groups used the Oxfordshire group's rating scale. Its main weaknesses were insensitivity in assessing the quality of audits and failure to measure team involvement. CONCLUSIONS: The rating system is effective educationally in helping practices improve and summatively for providing feedback to family health service authorities. The grid showed up weakness in the breadth of audit topics studied. IMPLICATIONS AND ACTION: Oxfordshire practices achieved targets set for 1991-2 but need to broaden the scope of their audits and the topics studied. The advisory group's targets for 1994-5 are for 50% of practices to achieve an audit in each of the areas of clinical care, access, communication, and professional values and for 80% of audits to include setting targets or implementing change.

Auditing audits: the method of Oxfordshire Medical Audit Advisory Group.

OBJECTIVES: To develop a systematic method for both summative and formative audit of practice audits, and to use the method to review Oxfordshire practice audits and to plan improvement. DESIGN: Development of a coding system for the audit cycle subsequently used prospectively to assess audits reported to medical audit advisory group coordinators on practice visits. SETTING: All 85 general practices in Oxfordshire, of which 80 were visited by Oxfordshire Medical Audit Advisory Group coordinators. MAIN OUTCOME MEASURES: Satisfaction of criteria for different levels of audit (full, partial, potential, planning or no audit) according to coding scores for practice audits. RESULTS: 46 (58%) practices were classified as doing audit, the remainder doing no audit or only collecting data for family health services authority returns. Of audits being undertaken, 55/102 (54%) included planning care or the setting of targets. CONCLUSIONS: The coding system offers the prospect of formative assessment for practices to help them improve their audits, and summative assessment for the family health services authority to satisfy the needs for professional accountability. Its use in Oxfordshire disclosed considerable deficiencies in the process of practice audit. IMPLICATIONS AND ACTION: Practices in Oxfordshire should improve their audits. The advisory groups target to March 1992 is for 50% of practices to be doing full or partial and 25% potential audit and half of the remainder planning audit. Practices are encouraged to include in their audit implementing change, planning care, and agreeing criteria for further assessment.

Darwin in disguise.

Darwinism appears in many more academic areas than just evolutionary biology. New disciplines are created out of its fusion with existing fields of study. However, this practise is criticised for a lack of evidence-based justification, and for adopting gene-oriented reductionism in the social sciences. This article briefly considers seven examples of new disciplines for which Darwinism has been appropriated. In each case, succinct background information precedes quotes provided for this purpose by a leading researcher.

Bravo Emma! Music in the life and work of Charles Darwin.

The long-term marital dance of Emma and Charles Darwin was set to the routine beat of an almost daily piano recital. Emma was a proficient pianist, and so a quality instrument was a welcome and appropriate house-warming present for their first marital home in London. That same piano accompanied the Darwins on their move to Downe before being upgraded for a newer model, which is still there, whilst another, cheaper piano may have played in Charles Darwin's work, particularly on earthworms. Whilst he lamented his own lack of musicality, Darwin revelled in his wife's prowess, a capacity that he recognised could be inherited, not least through observation of his own children. The evolution of musicality, he reasoned, was rooted in sexual attraction as a form of communication that preceded language.

Evaluation of cefaclor.

The chemistry, pharmacology, pharmacokinetics, bacterial spectrum, clinical use, dosage, adverse reactions, and dosage forms and cost of cefaclor are reviewed. Cefaclor, a congener of cephalexin monohydrate, is a new semisynthetic cephalosporin antibiotic. It is well absorbed when given orally on an empty stomach; absorption is delayed by the presence of food. Although metabolism may play a role in the disposition of cefaclor, elimination is primarily renal. Cefaclor's spectrum of activity is similar to that of cefalexin, including a wide range of gram-negative and gram-positive bacteria; in particular, Escherichia coli, Klebsiella spp., Proteus mirabilis, Salmonella spp., and Haemophilus influenzae are more susceptible to clinically achievable concentrations of cefaclor than cephalexin. Cefaclor has been demonstrated to be effective against beta-lactamase-producing H. influenzae resistant to ampicillin, but further studies are needed to establish the clinical significance of this activity. Efficacy of cefaclor has been demonstrated in urinary tract, upper and lower respiratory tract, and skin and soft tissue infections in adults and children as well as in pediatric otitis media. Adverse reactions, mostly gastrointestinal, are generally mild and occur in few patients. Usual doses are 250-500 mg every eight hours in adults and 20--40 mg/kg/day in children, although this pediatric dose may be two low for otitis media. Clinical superiority of cefaclor over less expensive antibiotics has not been demonstrated.

Physical linkage of the A-raf-1, properdin, synapsin I, and TIMP genes on the human and mouse X chromosomes.

Genes encoding the neuron-specific phosphoprotein synapsin I (SYN1), the glycoprotein tissue inhibitor of metalloproteinases (TIMP), the proto-oncogene A-raf-1 (ARAF1), and properdin (PFC), a positive regulator of the alternative pathway of human complement, lie within a conserved synteny encompassing the proximal short arm of the human X chromosome (Xp21.1-p11) and the centromeric end of the mouse X chromosome (A1-A5). We have used a mouse interspecific cross to demonstrate genetic linkage of Syn-1, Timp, and Araf and also show physical linkage, with Timp lying only 10 kb from Araf, within an intron of the Syn-1 gene. Detailed restriction mapping shows that Timp is transcribed in the same direction as Araf but in the opposite direction to the Syn-1 gene. Analysis of the corresponding region of the human X chromosome indicates a similar arrangement and in addition shows that the properdin gene lies within 5 kb of the 5' end of the synapsin I gene.

Mapping of the glycine receptor alpha 2-subunit gene and the GABAA alpha 3-subunit gene on the mouse X chromosome.

We have mapped the gene for the alpha 2-subunit of the inhibitory glycine receptor (Glra2) to the telomeric end of the mouse X chromosome by backcross analysis of a Mus musculus/Mus spretus interspecific cross. In addition, we have extended the mapping of the GABAA alpha 3-subunit receptor gene (Gabra3). A deduced gene order of cen-Cybb-Hprt-DXPas6-Gabra3-Rsvp-Gdx/Cf-8- Dmd-Pgk-1-DXPas2-Plp-DXPas1-Glra2-tel places Gabra3 proximal to the visual pigment gene Rsvp and Glra2 in the region of loci for hypophosphatemia (Hyp), steroid sulfatase (Sts), and the E1 alpha-subunit of pyruvate dehydrogenase (Pdha1). This establishes the XF region of the mouse X chromosome as homologous with the Xp22.1-p22.3 region of the human X chromosome and indicates the presence of an evolutionary breakpoint in the region of Xp21.3.